octreoscan® scintigraphy for gastro- entero-pancreatic ... · it is a nuclear medicine scan that...

OctreoScan®scintigraphy for gastro-

entero-pancreaticneuroendocrine tumours

August 1999

MSAC application 1003

Final assessment report

© Commonwealth of Australia 1999ISBN 0 642 41511 0

First printed August 1999

This work is copyright. Apart from any use as permitted under the Copyright Act 1968 nopart may be reproduced by any process without written permission from AusInfo. Requestsand inquiries concerning reproduction and rights should be directed to the Manager,Legislative Services, AusInfo, GPO Box 1920, Canberra, ACT, 2601.

Electronic copies of the report can be obtained from the Medicare Service Advisory Committee’sInternet site at:

http://www.health.gov.au/haf/msac

Hard copies of the report can be obtained from:

The SecretaryMedicare Services Advisory CommitteeDepartment of Health and Aged CareMail Drop 107GPO Box 9848Canberra ACT 2601

Enquiries about the content of the report should be directed to the above address.

The Medicare Services Advisory Committee is an independent committee which has beenestablished to provide advice to the Commonwealth Minister for Health and Aged Care on thestrength of evidence available on new medical technologies and procedures in terms of their safety,effectiveness and cost-effectiveness. This advice will help to inform Government decisions aboutwhich new medical services should attract funding under Medicare.

This report was prepared by the Medicare Services Advisory Committee. The report was endorsedby the Commonwealth Minister for Health and Aged Care on 9 August 1999.

Publication approval number: 2593

MSAC recommendations do not necessarily reflect the views of allindividuals who participated in the MSAC evaluation.

OctreoScan® scintigraphy for gastro-entero-pancreatic neuroendocrine tumours iii

Contents

Executive summary...................................................................................................... v

Introduction .................................................................................................................. 1

Background ..................................................................................................................2OctreoScan® scintigraphy for gastro-entero-pancreatic neuroendocrinetumours...............................................................................................................2Clinical need/burden of disease ..........................................................................5Existing procedures ............................................................................................6Comparator.........................................................................................................7Marketing status of the technology......................................................................8Current reimbursement arrangement...................................................................8

Approach to assessment ..............................................................................................9Review of literature .............................................................................................9Expert advice....................................................................................................12

Results of assessment ................................................................................................ 13Is it safe?...........................................................................................................13Is it effective?....................................................................................................13What are the economic considerations?.............................................................19Other considerations.........................................................................................22

Conclusions.................................................................................................................23Safety ................................................................................................................23Effectiveness.....................................................................................................23Cost-effectiveness .............................................................................................23Other considerations.........................................................................................23

Recommendations......................................................................................................25

Appendix A MSAC terms of reference and membership ........................................27

Appendix B Supporting committee ..........................................................................28

Appendix C Studies included in the review..............................................................29

Abbreviations ..............................................................................................................30

References................................................................................................................... 31

Bibliography ...............................................................................................................36

iv OctreoScan® scintigraphy for gastro-entero-pancreatic neuroendocrine tumours

Tables

Table 1 Carcinoid tumours ............................................................................................3

Table 2 Types of gastropancreatic endocrine tumours ...................................................4

Table 3 Prognosis in patients with Zollinger–Ellison syndrome related totumour resectability...........................................................................................7

Table 4 Location and source of studies........................................................................11

Table 5 Comparison of the ability of conventional imaging and ILOS to detectlesions in patients with GEP tumours .............................................................17

Table 6 Change in management after ILOS .................................................................17

Table 7 Clinical category after imaging.........................................................................18

Table 8 Lesions detected by applied imaging techniques for 30 carcinoid patients .......18

OctreoScan® scintigraphy for gastro-entero-pancreatic neuroendocrine tumours v

Executive summary

The procedure

OctreoScan® scintigraphy (OctreoScan) is a diagnostic test for gastro-entero-pancreatic(GEP) neuroendocrine tumours. It is a nuclear medicine scan that is capable of imagingthe entire body.

The Medicare Services Advisory Committee — its role andapproach to assessments

The Medicare Services Advisory Committee (MSAC) is a key element of a measure takenby the Commonwealth Government to strengthen the role of evidence in healthfinancing decisions in Australia. MSAC advises the Minister for Health and Aged Care onthe evidence relating to the safety, effectiveness and cost-effectiveness of new medicaltechnologies and procedures, and under what circumstances public funding should besupported.

A rigorous assessment of the available evidence is thus the basis of decision makingwhen funding is sought under Medicare. The medical literature on the new technology issearched and evidence is assessed. A team from the Australasian Cochrane Centre wasengaged to conduct a systematic review of literature on OctreoScan. A supportingcommittee with expertise in this area then evaluated the evidence and provided advice toMSAC.

Assessment of OctreoScan® scintigraphy for gastro-entero-pancreatic neuroendocrine tumours

The clinical studies undertaken to date on the sensitivity and specificity of OctreoScan allhave methodological limitations, including the failure to compare OctreoScan in ablinded trial with an acceptable ‘gold standard’, thus leaving open the possibility of bias.

There is some evidence that OctreoScan results in a change in management in aproportion of patients, but there are no randomised controlled trials available to supportthe improved outcomes for patients who receive OctreoScan.

Clinical need

GEP neuroendocrine tumours are relatively rare. Estimates of the incidence of carcinoidtumours vary between 7 and 13 cases per million population per year. The incidence ofclinically significant pancreatic endocrine tumours (PETs) is even rarer, with an estimatedincidence of 3.6 to 4 per million population per year. The prevalence in series of randomautopsies is surprisingly high (1%), indicating that the vast majority of tumours do notpresent clinically.

vi OctreoScan® scintigraphy for gastro-entero-pancreatic neuroendocrine tumours

In tumours that present clinically, the majority have metastatic disease at the time ofpresentation. The presence of hepatic and extrahepatic metastases is a major determinantof the management of disease. This is particularly so for gastrinomas, where thedevelopment of medication which is able to control the hypersection of gastric acid hasmeant that the growth and metastatic spread of disease is an important determinant oflong-term survival.

Insulinomas should be removed because there is a high rate of cure following removal.Surgery for carcinoid tumours is potentially curative but there is wide variation in thestudies of cure rates following surgery. Prognosis appears to be related to tumour size,although this is less so in midgut carcinoids.

The treatment of metastatic disease has become more important as the ability toeffectively treat the functional syndromes has increased. Previously, patients were morelikely to die as a result of the hormonal excess than from the tumour per se. Options forthe treatment of metastatic disease include chemotherapy, hormonal therapy withoctreotide, alpha-interferon, hepatic artery embolisation, and surgical debulking. Thetreatment of choice for carcinoid syndrome is octreotide therapy. Liver transplantationhas been attempted in a small number of cases, but hepatic recurrence is common and itis unclear whether transplantation prolongs survival.

Safety

OctreoScan appears to be safe at the currently recommended dosages.

Effectiveness

OctreoScan appears to have some theoretical advantages over other forms of imaging(for example it is able to image the entire body). However, it is difficult to assess the truesensitivity and specificity of OctreoScan because of the lack of data of sufficientmethodological quality. In comparison with existing methods of imaging, the test appearsmore sensitive, but the test has not been compared in a blinded fashion with anacceptable gold standard, and the types of tests with which it has been compared havevaried, even within the same study. Although the possibility of false positive results (andtherefore a specificity of less than 100%) has been discussed, none of the trials reporteddata that would allow us to calculate an estimate of specificity.

The major advantages of the technique are its ability to detect extrapancreatic tumoursand metastatic lesions outside of the abdomen and chest. Because OctreoScan images thewhole body, it may also detect an unsuspected multiple endocrine neoplasia type 1(MEN-1) tumour.

OctreoScan appears to be less sensitive in the detection of insulinomas, because of thelack of receptor sites on such tumours. Insulinomas also tend to be solitary tumours, notrequiring whole body imaging.

Because the imaging of a tumour may not result in a change in clinical management, atest of greater sensitivity and specificity may not result in better outcomes for patients.There is some evidence that OctreoScan results in a change in management in a

OctreoScan® scintigraphy for gastro-entero-pancreatic neuroendocrine tumours vii

proportion of patients. However, there is no evidence that this results in increased curerates or survival time.

Cost-effectiveness

It is not possible to accurately estimate the cost-effectiveness of OctreoScan, because ofthe lack of validated data on the accuracy of the test and its influence on clinicaloutcomes.

Recommendations

MSAC recommended that on the strength of evidence relating to OctreoScan, publicfunding should be supported for this diagnostic test:

• where there is a suspected GEP neuroendocrine tumour, based on biochemicalevidence, with negative or equivocal structural imaging from conventionalradiology (computed tomography or magnetic resonance imaging); or

• where surgically amenable disease has been identified, based on biochemicalevidence and conventional imaging, in order to rule out further metastaticdisease.

Since there is currently insufficient evidence relating to the use of OctreoScan for thepurposes of determining whether octreotide therapy is a viable therapeutic option, publicfunding should not supported at this time for this use.

OctreoScan® scintigraphy for gastro-entero-pancreatic neuroendocrine tumours 1

Introduction

The Medicare Services Advisory Committee (MSAC) has assessed OctreoScan®scintigraphy (OctreoScan)†, which is a diagnostic test for the detection and localisation ofgastro-entero-pancreatic neuroendocrine tumours.

MSAC evaluates new health technologies and procedures for which funding is soughtunder the Medicare Benefits Scheme in terms of their safety, effectiveness and cost-effectiveness, while taking into account other issues such as access and equity. MSACadopts an evidence-based approach to its assessments, based on reviews of the scientificliterature and other information sources, including clinical expertise.

MSAC’s terms of reference and membership are shown in Appendix A. MSAC is amultidisciplinary expert body, comprising members drawn from such disciplines asdiagnostic imaging, pathology, surgery, internal medicine and general practice, clinicalepidemiology, health economics and health administration.

This report summarises the current evidence of the effectiveness of OctreoScan for thedetection and localisation of gastro-entero-pancreatic neuroendocrine tumours.

† OctreoScan® is a registered tradename of Mallinckrodt Medical, Petten, Netherlands

2 OctreoScan® scintigraphy for gastro-entero-pancreatic neuroendocrine tumours

Background

OctreoScan® scintigraphy for gastro-entero-pancreaticneuroendocrine tumours

Neuroendocrine tumours are derived from neural crest cells, which develop in theembryo and migrate throughout the body. Neuroendocrine tumours include thecarcinoids tumours, pancreatic endocrine tumours, melanomas, phaeochromocytomasand medullary thyroid carcinomas. Such tumours are histologically similar and also sharecytochemical features. Gastro-entero-pancreatic (GEP) neuroendocrine tumours includethe carcinoid tumours and the pancreatic endocrine islet cell tumours. Both types oftumour are relatively rare. The majority of such tumours are malignant but are frequentlyslow growing.

Carcinoid tumours

Carcinoid tumours commonly originate in one of four sites: bronchus, appendix, rectumand jejuno–ileum.1 For the purposes of this review, carcinoid tumours that originate inthe gastrointestinal system have been included as GEP tumours.

Carcinoid tumours that originate in the midgut (jejunum, ileum, appendix, Meckel’sdiverticulum and ascending colon) often produce high levels of hormones, which cause acharacteristic clinical syndrome known as carcinoid syndrome, the main feature of whichis attacks of flushing. This may be accompanied by diarrhoea, pain, wheezing,lacrimation, itching, palpitations, or facial or conjunctival oedema. The attacks may occurspontaneously or be triggered by stress, alcohol, exercise, or food intake. Cardiacmanifestations have been reported in 11–56% of patients, primarily due to fibrousdeposits which cause constriction of the heart valves.2,3 For patients without systemicfeatures, the most common clinical presentation is that of periodic abdominal pain. Asummary of some of the features of carcinoid tumours is shown in Table 1.

Pancreatic endocrine tumours

The classification of pancreatic endocrine tumours (PETs) is shown in Table 2. PETs aredefined as functional when they secrete hormones that produce a clinical syndrome. Forexample, a functional gastrinoma causes Zollinger–Ellison syndrome (ZES), which is asevere form of stomach and duodenal ulceration. Some of the clinical features of themore common PETs are described below.

Gastrinomas

The most common presenting symptom of a gastrinoma is abdominal pain due to acidsecretion. The disease is suspected for patients with peptic ulcer plus diarrhoea, familialpeptic ulcer, peptic ulcer in unusual locations and recurrent or resistant peptic ulcer.Many patients with gastrinomas have diarrhoea and in 15 to 18% of patients it is the onlypresenting symptom.4 Gastrinomas frequently have occult metastases and may havemultifocal primary lesions.


Table 1 Carcinoid tumours

Tumour location % of totalIncidence of

metastases (%)Incidence of carcinoid

syndrome (%)

Foregut

Oesophagus <1 – –

Stomach 2 22 9.5

Duodenum 2.6 20 3.4

Pancreas <1 20 20

Gall bladder <1 33 5

Bile duct <1 – -

Ampulla <1 14 –

Larynx <1 50 –

Bronchus 11.5 20 13

Thymus 2 25 –

Midgut

Jejunum 1.3 35 9

Ileum 23 35 9

Meckel’s diverticulum 1 18 13

Appendix 38 2 <1

Colon 2 60 5

Liver <1 – –

Ovary <1 6 50

Testis <1 – 50

Cervix <1 24 3

Hindgut

Rectum 13 3 –Source: De Vita VT, Hellman S and Rosenberg SA (eds.)5

Insulinomas

Insulinomas were first recognised by Whipple who described a triad of symptomsconsisting of hypoglycaemia associated with blood sugar levels less than 50 mg/dL, withrelief of symptoms following ingestion of glucose.6 Insulinomas are frequently solitarybenign tumours.

Nonfunctional pancreatic endocrine tumours

Nonfunctional PETs do not secrete a peptide hormone causing any specific clinicalsymptoms. Many of the nonfunctional PETs present late, principally with symptoms dueto obstructive or mass effects. They are usually quite large and locally invasive at the timeof presentation.5

Multiple endocrine neoplasia type 1

Pancreatic endocrine tumours can form part of the syndrome of multiple endocrineneoplasia type 1 (MEN-1). This is an autosomal dominant disease with tumoursinvolving the pituitary gland, parathyroid glands and pancreatic islets. Ppomas are themost common pancreatic endocrine tumours in MEN-1 patients, but 82% also develop afunctional PET.7


Table 2 Types of gastropancreatic endocrine tumours

Tumour name Syndrome name Hormone producingsymptoms

Malignant (%) Location

Ppoma Ppoma None >60 Pancreas

Non functioning Nonfunctioningpancreatic endocrinetumour

None >60 Pancreas

Symptoms due to released hormones

Gastrinoma Zollinger–Ellisonsyndrome

Gastrin 60–90 Pancreas (30–60%)Duodenum (30–43%)Other (10–20%)

Insulinoma Insulinoma Insulin 10–15 Pancreas (>99%)

VIPoma Pancreatic choleraVerner-Morrison(WDHA – waterydiarrhoea hypkalemiaachlorhydria)

Vasoactive intestinalpeptide (VIP)

80 Pancreas (90%)Adrenal (10%)

Glucagonoma Glucagonoma Glucagon 60 Pancreas (>99%)

Somatostatinoma Somatostatinoma Somatostatin Pancreas (56%)Upper small intestine(44%)

GRFoma GRFoma Growth hormone-releasingpeptide (GRF)

30 Pancreas (33%)Lung (53%)Small intestine(10%)Other (7%)

ACTHoma Ectopic Cushing’ssyndrome

Adrenocorticotrophichormone (ACTH)

>95(pancreatic)

Pancreas (4–16%)

Source: De Vita VT, Hellman S and Rosenberg SA (eds.)5

How it works

OctreoScan is a diagnostic test for GEP neuroendocrine tumours. It is a nuclearmedicine scan that is capable of imaging the entire body.

The technique, which was first described by Krenning et al in 19898, is based on thepresence of high affinity binding sites for somatostatin receptors on the surface of mostGEP tumours9,10. A radionuclide is attached to a somatostatin analogue called octreotide.The radiolabelled octreotide is injected into the patient, and radioactivity concentrates attumours with somatostatin receptors and in organs that excrete the radionuclide.Scintigraphic imaging with a gamma camera is used to locate concentrations ofradioactive activity, and thus localise tumour sites.

Initially, [123I-Tyr3] was used to label octreotide, but this radionuclide had the followingshortcomings:

• the labelling of [Tyr3]-octreotide with 123I is a difficult process requiring advancedskills;

• high specific activity radiolabelled sodium iodide (Na123I) is needed for theprocedure, which is expensive and difficult to obtain;

• the timing of the labelling and scanning must coincide with the production anddelivery schedule for Na123I because of its short half life (13.2 hours); and


• because [Tyr3]-octreotide is largely excreted by the liver, biliary system andintestines, these organs have high levels of radioactivity, which makesinterpretation of images difficult.11

In OctreoScan, the octreotide is radiolabelled with the indium (In) derivative [111In-DTPA-D-Phe1]. This radionuclide has advantages over [123I-Tyr3]-labelled octreotide inthat it is comparatively easy to prepare and more generally available. In addition, it has alonger half life (2.8 days), which means scanning does not have to immediately followproduction. Also, as it is rapidly excreted by the kidneys, there is much less interferencefrom radioactivity in the intestines 12.

OctreoScan imaging is typically preceded by administration of laxatives to reduce thechance of radioactivity in the intestinal system. Planar antero–posterior whole bodyimages are usually obtained 4 and 24 hours after injection of In-labelled octreotide. Singlephoton emission computerised tomography (SPECT) is often performed as well, usuallyat 24 and occasionally at 48 hours after the injection. SPECT is able to differentiate moreeasily between areas of pathological uptake and physiological uptake in the abdomen. Itcan also help to discriminate between mesenteric and bone lesions. Extra planar imagesmay be obtained from areas of specific interest, using longer exposure time for moreeasily interpreted imaging.

Intended purpose

OctreoScan was approved by the Therapeutic Goods Administration (TGA) on 30 May1996 for the localisation of GEP neuroendocrine tumours.

The information gained from scintigraphy of GEP tumours can be used for thefollowing purposes:

• to determine the stage and extent of the disease;

• to localise a solitary tumour which may then be evaluated for resection;

• to plan palliative resection; and

• to evaluate the potential value of medical treatment with somatostatin analogues.

Clinical need/burden of disease

Incidence/prevalence of GEP neuroendocrine tumours

GEP neuroendocrine tumours are relatively rare. Estimates of the incidence of carcinoidtumours vary between 7 and 13 cases per million population per year.13,14 The incidenceof clinically significant PETs is even rarer, with an estimated incidence of 3.6 to 4 permillion population per year.15,16,17 The prevalence of the tumours in series of randomautopsies is surprisingly high (1%), indicating that the vast majority of tumours do notpresent clinically.


In tumours that do present clinically, the majority have metastatic disease at the time ofpresentation. The presence of hepatic and extrahepatic metastases is a major determinantof the management of disease. This is particularly so for gastrinomas, where thedevelopment of medication that is able to control the hypersection of gastric acid hasmeant that the growth and metastatic spread of disease is an important determinant oflong-term survival.18

Surgical removal of GEP neuroendocrine tumours

There is a lack of controlled studies that investigate whether surgical resection of a GEPtumour alters the natural history of the disease. A nonrandomised controlled trial at theNational Institutes of Health (NIH) in the United States followed 98 patients with ZESwho had the tumour resected and 26 patients who were treated medically. 19 Three in thesurgical group developed liver metastases and six in the medical group (P<0.003). Twodeaths occurred in the medical group due to metastatic disease and no disease-specificdeaths occurred in the surgical group. This was not a randomised controlled trial, butthere was no significant difference between the two groups on clinical or laboratorycharacteristics, or the duration of disease at baseline.

Other case-series data have indicated improvements in survival rates after resection of agastrinoma (see Table 3). Case-series data have also indicated that there has been animprovement in the cure rate following surgical resection of gastrinomas in recent years.This can be attributed to improvements in antisecretory treatment, and improvements inpreoperative and intraoperative localisation.

Insulinomas should be removed because there is a high rate of cure following removal.Surgery for carcinoid tumours is potentially curative but there is wide variation in thestudies of cure rates following surgery. Prognosis appears to be related to tumour size,although this is less so in midgut carcinoids20.

The treatment of metastatic disease has become more important as the ability toeffectively treat the functional syndromes has increased. Previously, patients were morelikely to die as a result of the hormonal excess than from the tumour per se. Options forthe treatment of metastatic disease include chemotherapy, hormonal therapy withoctreotide, alpha-interferon, hepatic artery embolisation, and surgical debulking. Thetreatment of choice for carcinoid syndrome is octreotide. Liver transplantation has beenattempted in a small number of cases, but hepatic recurrence is common and it is unclearwhether transplantation prolongs survival.

Existing procedures

The diagnosis of a GEP tumour is usually made by detection of high levels of secretedhormone in serum. This may also require a stimulation test, such as the calcium test forinsulinoma tumours or secretin test for gastrinoma tumours. Primary lesions may also beconfirmed by biopsy and histological examination. After confirmation of the diagnosis,the patient is evaluated for management of the tumour. A combination of imagingmodalities is used. Investigations that are used routinely are computed tomography (CT)scan, endoscopic and upper abdominal ultrasound and magnetic resonance imaging(MRI). Angiography and bone scans may also be used. In the past it has often beendifficult to detect and localise GEP tumours.


Table 3 Prognosis in patients with Zollinger–Ellison syndrome related to tumour resectability

Tumour status Survival rate (%)

Patients 5-year 10-year Study

No tumour found 13 100 100 Malagelada et al 198321

6 100 – Zollinger et al 198422

10 90 90 Stabile andPassaro198523

8 ND 63 Zollinger 198524

16 90 ND Norton et al 199125

15 93 (70–99) 84 (56–96) Weber et al 1995b18

Tumour resected 7 100 100 Malagelada et al 198321


10 90 90 Stabile and Passaro198523

33 69 62 Ellison et al 198726


53 100 (87–100) 96 (87–100) Weber et al 1995b18

Tumour incompletely 10 75 20 Malagelada et al 198321

resected or recurrence 7 14 – Zollinger et al 198422


34 100 (84–100) 93 (68–99) Weber et al 1995b18

Unresectable 13 80 – Malagelada et al 198321


14 40 30 Stabile 198523

15 20 – Norton et al 198627


36 53 (35–69) 30 (14–52) Weber et al 1995b18

ND = no data obtained at 10 years; – = no data as yetNumbers in brackets are 95% confidence intervals

Comparator

The main purpose of imaging in patients with GEP pancreatic neuroendocrine tumoursis to localise the disease and to determine whether hepatic and extrahepatic metastasesare present. In the major studies assessing the clinical effectiveness of OctreoScan, thetechnology has been compared with ‘conventional imaging modalities’ (CIM). However,these modalities have varied between sites and the types of tumours being investigated.The imaging techniques used in the diagnosis of GEP tumours are described brieflybelow.

UltrasoundAbdominal ultrasound is frequently used as a first-line investigation in the diagnosis ofGEP tumours but is relatively insensitive in the detection of GEP tumours. In one series,abdominal ultrasound detected only 15% of gastrinomas from 1 to 3 cm in size28.

Endoscopic ultrasoundThis form of ultrasonography is a more sensitive means of locating tumours in theduodenum and pancreas. In one series it detected more than 60% of gastrinomas andpancreatic tumours. The sensitivity of the technique, however, is extremely operator


dependent29. Routine endoscopy is a relatively insensitive means of localising GEPtumours. Even gastrinomas are often not seen on routine endoscopy because they areoften submucosal.

Computed tomographyThe ability of CT scans to detect GEP tumours varies depending on the location of thetumour, the type of tumour and the size of the tumour. It is relatively more sensitive fordetecting insulinomas and less sensitive for detecting gastrinomas. Contrast injectionsand helical scanning may improve the sensitivity of CT scans. In several of the studies,the intravenous contrast agent iopamidol 30% was used.

Magnetic resonance imagingImprovements in MRI technology has resulted in better results compared to otherroutine imaging techniques for the detection of GEP tumours.30 Delayed T1 images atleast 5 minutes after contrast enhancement are able to distinguish malignant from benignhepatic lesions. However, artifacts caused by any movement of the patient reduce thesensitivity of MRI, especially for small pancreatic tumours.

AngiographyAngiography is frequently used if surgery is planned or if the results of other forms ofimaging are equivocal. Imaging is achieved by injection of the splenic, superiormesenteric, gastroduodenal and hepatic arteries with contrast material. Digitalsubtraction angiography improves sensitivity and specificity.

Bone scanThis is a nuclear medicine scan for the detection of bone metastases.

Other methodsOther methods that are also used to localise GEP tumours include intraoperativeultrasound, intraoperative transillumination, portal venous sampling, intra-arterialstimulation with calcium (for insulinomas) and intra-arterial stimulation with secretin (forgastrinomas). These techniques can be useful for detecting occult tumours. For ethicalreasons relating to their invasive nature, however, these methods have not been used inlarge studies of unselected patients with GEP tumours.

Marketing status of the technology

OctreoScan was approved by the TGA on 30 May 1996 for the localisation of GEPneuroendocrine tumours.

Current reimbursement arrangement

Currently there is no specific Medicare Benefits Schedule (MBS) item number forOctreoScan.


Approach to assessment

Review of literature

MSAC reviewed the literature available on OctreoScan and provided expert advice. Themethodology used in this review of the evidence of literature on the effectiveness andsafety of OctreoScan has followed the methods outlined in the Cochrane CollaborationHandbook and Irwig et al (guidelines for meta-analyses evaluating diagnostic tests) asclosely as possible.31,32

Literature search

The medical literature was searched to identify relevant studies and reviews, detailsfollow:

• Medline (1989 to November 1998)– MeSH (keyword system): octreotide — diagnostic use– Text: octreotide, OctreoScan, scintigraphy (filtered by neuroendocrine)

• Cochrane Library (issue 4, 1998)– Text: octreo*

• EMBASE (1989 to December 1998)– Text: octreotide or OctreoScan (filtered by diagnosis and neuroendocrine)

• Healthstar (1989 to December 1998)

• National Health Service (NHS) Database of Economic Evaluations (searchedDecember 1998)

• Best Evidence (1998 issue)– Text: octreo*

(where: * = wildcard)

Internet sources including Oncolink, International Society for Technology Assessment inHealth Care (ISHTAC) and other health technology assessment sites were examined.

Searches were restricted to the period after 1989, since the relevant OctreoScantechnology was not available before this time.

Reference lists of reviews and other articles were searched.

In addition, data was available from unpublished trials that formed part of the EuropeanMulticentre Trial (EMT) conducted by Mallinckrodt Medical Petten, a manufacturer ofOctreoScan technology (OctreoScan).


Inclusion/exclusion criteria

Citations that discussed the use of OctreoScan in tumours other than GEP tumours werefirst excluded. The abstracts of the remaining 211 studies were assessed and a list of 97primary studies was compiled for possible inclusion in this review (see Bibliography).

To qualify for inclusion, studies had to be primary studies comparing OctreoScan withany other form of detection and/or localisation of GEP neuroendocrine tumours.

Out of these 97 studies, those with fewer than 25 patients (53 studies), or for which anEnglish language version of the study was not available (7 studies) were not consideredfurther.

The majority of the studies reported on the ability of OctreoScan to detect lesionscompared to other forms of imaging. The results from these studies were commonly inthe form of the number of sites detected by OctreoScan versus the number of sitesdetected by conventional imaging modalities. Most studies reported the number lesionsbut some studies reported the number of patients. The number of patients in whomadditional sites were detected was also reported.

Most of the potentially eligible studies fell into three main categories, either as part of theUniversity Hospital Rotterdam study (UHR), the United States National Institutes ofHealth (NIH) prospective study of patients with ZES, or the European Multicentre Trial(EMT). The European Multicentre Trial was sponsored by Mallinckrodt Medical Petten,a manufacturer of OctreoScan technology (OctreoScan) at 15 centres between August1991 and May 1993.

Multiple publication of data derived from the same patient pool or cumulatively, withoutcross-reference, is common practice among the investigators active in this field. Someinvestigators were contacted and clarification was obtained in some cases, but not all.This made it very difficult to summarise the data and precluded meta-analysis. The EMTdatabase was particularly impenetrable. Several investigators separately published thefindings obtained from patients studied at their institutions. These reports duplicate oroverlap patients included in the overall EMT summary report by Krenning et al199633.Mallinckrodt files document the studies undertaken at 11 of the 15 centres involved inthe EMT. Two studies documented in the Mallinckrodt files have also been reported infive publications, as far as we can determine34,35,36,37,3839. Four studies have been reportedin seven publications that, as far as we can determine, were originally part of the EMTbut are not documented in the Mallinckrodt file40,41,42,43,44,45,46.

Table 4 shows the location and source of the studies we identified as potentially eligiblefor inclusion in this review and illustrates the problem of multiple publication from thesame study and partial and possible overlap of studies.

Taking into consideration duplicate publication, adequacy of test protocol and availabilityof useful data, four studies were selected for inclusion in this review. These studies areindicated in Table 4 and further details are given in Appendix C. Overview summaries ofthe European studies (EMT and UHR) by Krenning et al33,52 were also considered.


Table 4 Location and source of studies

Location SourceUniversity Hospital Dijkzigt, Rotterdam (UHR) Kwekkeboom et al 199347 (n=30)*

Kwekkeboom and Krenning 199648 (n=30) *Kwekkeboom et al 199649 (n=30)*Known overlap (same study)Krenning et al 199311 (n=128)Possible overlap

National Institutes of Health, Bethesda, USA (NIH) Gibril et al 199630 (n=80)Termanini et al 199750 (n=122)*Known overlapJensen et al 199751 (n=122)Probable overlapAlexander et al 199852 (n=35)Probable overlap

European Multicentre Trial (EMT) Krenning et al33 (n= 350)Overview of other EMT studies

EMT/UHR Krenning et al 1994a,b53

Overview of EMT and UHR studies

EMTStudy centre 1: Georg-August Universität, Gottingen Nauck et al 199439 (n=34)

EMTStudy centre 2: University of Louvain Medical School, Louvain Pauwels et al 199440 (n=30)*

Jamar et al 199541 (n=38) Jamar et al 199541 (n=47) Possible overlap

EMTStudy centre 3: Universitäts Klinikum, Berlin Scherubl et al 199342 (n=40)

Wiedenmann et al 199443 (n=74)Probable overlap

EMTStudy centre 4: Philipps Universität, Marburg Joseph et al 199344 (n=85)

Kisker et al 199745 (n=55)Possible overlap

EMTStudy centre 7: Groupe Hospitalier Bichat, Paris Cadiot et al 199734

Lebtahi et al 199835

Probable overlap

EMTStudy centre 13: University of Uppsala, Uppsala Westlin et al 199236 (n=40)

Westlin et al 1993a,b37 (n=40)Known overlap (same study)Kälkner et al 199538 (n=100)Possible overlap

EMTStudy centre 5: Hôpital Neuro-Cardiologique, LyonStudy centre 6: Universitätsspital Zürich, ZurichStudy centre 7: Groupe Hospitalier Bichat, ParisStudy centre 8: St Bartholomew’s Hospital, LondonStudy centre 9: Nuklearmedizinische Klinik der Technischen Universität Munchen,MunichStudy centre 10: Hammersmith Hospital, LondonStudy centre 11: Westfalische Wilhelm Universität Münster, MünsterStudy centre 12: Hadassah University, JerusalemStudy centre 13: University of Uppsala, UppsalaStudy centre 14: Academisch ziekenhuis Leiden, LeidenStudy centre 15: Sahlgrenska Sjukhuset, Gothenberg

Unpublished:Mallinckrodt Medical Pettenn (n=247).

Groupe Hospitalier Bichat, Paris Lebtahi et al 199654 (n=160)Lebtahi et al 199755 (n=160)*Probable overlap with each other, no overlapwith EMT

* Studies included in the review (see Appendix C for further details)


Extraction of data

Data were extracted independently from the four included studies by two reviewers. Anydifferences found in the data extracted were discussed or referred to a third reviewer.

Assessment of quality

Each of the studies included in this review was assessed for quality using the followingthree criteria based on recommendations for assessing the scientific validity of estimatesof diagnostic accuracy: 32

• the study examined a consecutive series or a random selection of a consecutiveseries of patients;

• all participants in the study received both OctreoScan and a comparator test; and

• the results for each test were interpreted without knowledge of the results of theother test.

Expert advice

A supporting committee, including members with expertise in relation to management ofGEP neuroendocrine tumours, was convened to assess the evidence on this procedure.In selecting members for supporting committees, MSAC’s approaches appropriatemedical colleges, associations or specialist societies for nominees. Membership of thesupporting committee is shown at Appendix B.


Results of assessment

Is it safe?

OctreoScan should only be used by qualified personnel with the appropriate governmentauthorisation for the use and manipulation of radionuclides. OctreoScan may bereceived, used and administered only by authorised persons in designated clinical settings.

The diagnostic imaging dose of octreotide for OctreoScan is ten-times lower than thetherapeutic dose. It is therefore not expected that imaging will result in significantsomatostatin effects.

The most extensive data on adverse effects were reported in the European MulticentreTrials (EMT). In these 15 trials, all patients were monitored for heart rate, blood pressureand respiratory frequency, 15 minutes and 10 minutes before injection and at five and 30minutes after injection. Clinical signs and symptoms were also recorded. Laboratoryanalyses of haematology, serum biochemistry and urinalysis before and four hours afterinjection were also performed.

There were 12 adverse effects reported from the total of 482 patients. This represented2.3% of all administered doses. Of these 12 patients, nine were evaluated in the trials.Two patients were excluded in retrospect due to protocol violations and one excludedafter it was confirmed the patient did not have a GEP neuroendocrine tumour. Therewere two fatal incidences, which separate expert opinions agreed were not related to theinfusions.

The adverse reactions included sweating, hypotension, headache, pain in limbs, fever,flushes, nausea, stomach spasms, weakness and dizziness. Of these 12 adverse reactions,none required treatment and all were of a relatively short duration.

No clinically significant changes in vital signs or urine composition were observed. It wasreported that some statistically significant changes in haematology and serumbiochemistry were observed, but none of these were clinically significant and there wereno overall trends.

Is it effective?

For diagnostic tests, ‘effectiveness’ has two components: the accuracy of the test and theeffectiveness of patient management options if a positive test result is obtained.

Accuracy of the test

The accuracy of a diagnostic test is measured primarily by its sensitivity and specificity,which are measured as follows:

Sensitivity = true positive resultstrue positive + false negative results

Specificity = true negative resultstrue negative + false positive results


Ideally, the sensitivity and specificity are calculated by comparison with a ‘gold standard’test (that is, one with a sensitivity and a specificity as close to 100% as possible). In thecase of GEP tumours, the gold standard is histological diagnosis of surgical specimens.

In the conventional terminology regarding diagnostic test evaluation, sensitivity andspecificity refer to the ability of the test to differentiate between those who have thedisease in question and those who do not. However, in all the studies located the datareported does not include whether the patients who were studied have the disease or not.Instead, the studies report data on whether OctreoScan is able to detect the primary ormetastatic lesions of the disease compared with the ability of CIM to detect such lesions.The use of the terms ‘false positive’ and ‘false negative’ is therefore problematic as thepresence or absence of lesions from either OctreoScan or CIM does not exclude orconfirm the presence of disease.

In some of the studies, the possibility of OctreoScan resulting in false positive and falsenegative results was discussed. False positive results can occur in the presence ofinflamed tissues (such as sarcoidosis, inflammatory bowel disease and rheumatoidarthritis), meningiomas, metastatic breast cancer, neuroblastomas, oat cell carcinoma ofthe lung and ovarian tumours. False negative results occur because of the lack ofsomatostatin receptor sites on the tumour, in lesions less than 1 cm, lesions which areclosely adjacent and in lesions hidden by physiological enhancement of the liver andkidneys during excretion of the drug. While these issues were discussed, none of thestudies reported numbers of cases and it was therefore impossible to calculate thesensitivity and the specificity of the test in the conventional meanings of those terms.

In all of the eight studies that have been included in the review, the ability of OctreoScanto detect the presence and location of lesions has been compared with a combination ofCIM. Even within the trials, the combination of imaging modalities was not standard andvarious combinations of the modalities were used in different patients. Estimates ofsensitivity and specificity based on comparison with a test that is not an independentgold standard can be misleading56.

Patient outcomes

Even though all of the studies reported data on the ability of OctreoScan to detect andlocalise lesions, this is not a good indicator of the usefulness of the test. If surgery is notan option, localisation of a lesion may have no effect on management. For example, if apatient has known metastatic disease, the ability to detect additional lesions will have noeffect on clinical management. Therefore an increase in ‘sensitivity’ as reported in thestudies may not translate into improved outcomes for the patient. Where it was possiblefrom the data reported, we attempted to determine the ability of OctreoScan todifferentiate patients with a primary lesion only, hepatic metastases and extrahepaticmetastases, and compared this with the data reported in the same studies on the ability ofCIM to make the same differentiation.

The ideal method for assessing patient outcomes after using a diagnostic test, is arandomised controlled trial examining outcomes of importance to patients, such assurvival times and quality of life, in those who have had the test compared with thosewho have not had the test. No trial of this sort was available.


Another potential use of OctreoScan is to predict whether a patient with metastaticdisease may benefit from treatment with the somatostatin analogue, octreotide.

Quality assessment

Study quality was poor, or at least poorly reported, in most cases. Only two studies wereassessed to be adequate on all three of the quality criteria applied.50,54 In the others, it wasunclear whether a consecutive series of patients was examined, or if there was blindedinterpretation of the results from OctreoScan and CIM.

None of the studies provided data that could be used to determine sensitivity andspecificity of OctreoScan. Most trials reported what they referred to as ‘sensitivity’, butthis was a misnomer. What they in fact reported was the percentage detection rate interms of patients or lesions.

Several aspects of the design and conduct of the studies impact on the reliability of thedata that they provide. One of these is the test protocol, which was highlighted byKrenning et al33 in a comparison of the UHR study and the EMT study.

The question about the adequacy of the test protocol was raised because the OctreoScandetection rate of 80% on a patient basis in the EMT study was lower than expected. Aprevious study of 130 patients with GEP neuroendocrine tumours at the ErasmusUniversity Hospital, Rotterdam (UHR), showed an 88% detection rate11. The authorssuggested that the differences may have occurred because the scanning procedures usedat some centres in the EMT study were inadequate (EP Krenning, personalcommunication). Some patients in the EMT study may have received an inadequate doseof radionuclide compared with a minimal dose of 200 megabecquerels (MBq) in theUHR study. Furthermore, abdominal SPECT was not performed in all patients in theEMT study and lateral planar abdominal scanning is not an adequate substitute forSPECT (EP Krenning, personal communication). This may explain why only 73% ofgastrinoma patients had a positive scan compared with 12/12 patients in the UHR study.

The Mallinckrodt files also point out that some investigators in the EMT study deviatedfrom the sponsor’s protocol in terms of dose and timing of the test and scanningprocedure. It is not possible without individual patient data to determine which patientsat which study centres were examined by a protocol for which there is empirical evidencethat it was inadequate. Professor Krenning advises that the EMT study not be used as abasis for assessing the appropriateness of OctreoScan for detecting GEP tumours(EP Krenning, personal communication).

Results

An overall summary of the results from the EMT was published by Krenning et al 199633

that compared the findings of the study with those from the UHR study.46,47 Accordingto the summary report, 399 patients were enrolled in the EMT, 350 met the inclusioncriteria and were retained for the analysis of efficacy. Patient follow-up data was updatedin April 1994 and re-analysed in May 1994. Conventional imaging modalities includedultrasound, CT, MRI, angiography, and biopsy or surgery. It is not clear from the reports,however, which patients did and did not have surgical investigation.


In the EMT study by Pauwels et al,40 42 patients had no previously known tumourdetected by CIM, OctreoScan was positive in 11/42 patients and 12/16 of the lesionsdetected were confirmed as true positive findings. Of 178 patients in the EMT study witha single known lesion, OctreoScan demonstrated multiple tumour sites in 62 of thesepatients and 60% of the lesions detected were confirmed.40 The impact on clinicalmanagement was assessed by questionnaires completed by investigators on 235 patientsfrom 13 of the centres participating in the EMT study. Overall, OctreoScan findings ledto changes in the clinical management of 94/235 patients (40%). Scintigraphy findingshad an impact on the surgical decision in 29 cases; surgery was performed in 21 cases andcancelled in eight. Octreotide therapy was started in 47 patients and 18 patients had theirdose modified.40

Studies including patients with insulinoma report lower scintigraphy detection rates forthis type of tumour than with other GEP tumour types. Comparing the EMT results40

with the UHR results,46,47 detection of GEP tumours expressing a high concentration ofoctreotide receptors, such as carcinoids, glucagonoma and nonsecreting pancreaticendocrine tumours, was high in both studies. According to the authors, the differences inscanning procedures are apparently not that significant for these types of tumours. Theresults from the two studies, however, show large differences in the detection rate ofgastrinomas and insulinomas on a patient basis.40,46,47

In the EMT study, eight patients strongly suspected of having a gastrinoma had apositive CIM and negative scintigrams. CIM tumour localisation was pancreas (3),duodenum (3), liver (1) and liver hilus (1). In 6/8 of these patients the dose was between100 and 129 MBq and/or no abdominal SPECT had been performed. In 17 CIMnegative patients strongly suspected of having a gastrinoma, octreotide scintigraphyfound lesions in six patients. CIM and scintigraphy combined localised lesions in 56/67patients suspected of having a gastrinoma.40

In the EMT study, 17/24 patients suspected of having an insulinoma had a lesion foundby CIM, whereas 9/17 had a positive scintigram.40 In 3/8 patients with a negativescintigram, the dose was between 103 and 123 MBq and no abdominal SPECT had beenperformed. OctreoScan found a lesion in 3/7 CIM-negative patients. CIM andscintigraphy combined localised lesions in 19/24 patients suspected of having agastrinoma. The authors suggest that this could be due to differences in scanningprocedures used in the two studies. In the EMT, false negative scintigrams wereespecially obtained in patients who received a lower dose and who were not investigatedwith SPECT. If SPECT was used, the counting time per view was shorter than used inthe Rotterdam study.33

A summary of the results is in Table 5.


Table 5 Comparison of the ability of conventional imaging and OctreoScan to detect lesions inpatients with GEP tumours

Studyn CIM positive OctreoScan

positive

CIM andOctreoScanboth positive

CIM andOctreoScanbothnegative

Pauwels et al 199440 (EMT) 30 24 (80%) 26 (87%) 23 (77%) 3 (10%)

Lebtahi et al 199754 160 114 (71%) 125 (78%)- 97 (61%) 18 (11%)

Termanini et al 199749 (NIH) 122 76 (62%)All gastrinoma

75 (61%) 122 (100%) 29 (24%)

Kwekkeboom et al 1993, 199646,47

(UHR)30 21 (70%)

All carcinoids24 (80%) 21 (70%) 6 (20%)

CIM = conventional imaging modality; OctreoScan = indium-labelled octreotide scintigraphy; n= number of patients

In two of the included studies, the effect of OctreoScan on the clinical management ofpatients with GEP tumours was studied. Termanini et al (NIH)49 prospectively enrolled122 consecutive patients with Zollinger–Ellison syndrome. The treatment plan wasdetermined after the results of CIM were performed (CT scan, MRI, ultrasound, selectiveangiography and bone scan). OctreoScan was then performed (without knowledge of theCIM results) and then the plan of treatment again determined. It would appear from theresults that the second treatment plan was decided with knowledge of both sets ofresults, rather than knowledge of the OctreoScan results alone. The results of the studyare shown in Table 6.

Table 6 Change in management after OctreoScan

Clinical category at time of scan

Scintigraphy result whichchanged management

Initialevaluation

(n=17)

Curedafter

surgery(n=18)

Not curedafter

surgery(n=50)

Nosurgery

(n=12)

Metastaticliver

disease(n=25)

Total(n=122)

Only test positive for: – primary lesion 1 – 11 3 – 15 – liver metastases – – 2 – – 2

– bilateral liver metastases – – – – 3 3

– bone metastases – – – – 2 2

Clarified lesion seen on CIM 7 4 11 3 8 33

Identified additional metastases – – – – 2 2

Total with changed management 8 4 24 6 15 57n = number of patientsSource: Termanini et al 1997 (NIH study)49

The second study by Lebtahi et al (Paris)54 reported on the impact of OctreoScan todifferentiate between patients with primary lesions, hepatic metastases and extrahepaticmetastases. The study analysed data from 160 consecutive patients who presentedbetween 1992 and 1995. The breakdown of patients by tumour was 78 patients withZollinger–Ellison syndrome, 38 patients with a carcinoid tumour and 44 patients withother types of neuroendocrine tumours. Histological confirmation of the tumour wasobtained in 142 of the 160 patients. 108 of the patients were investigated as part ofprimary staging of the tumour and 52 patients were investigated for recurrence aftersurgery. Because the data are presented in a way that the categories could be overlapping,it is difficult to give clear results but the results of staging appeared to be as shown inTable 7.


Table 7 Clinical category after imaging

Category After CIM After both CIM and OctreoScan

No known lesion 46 4?

Primary lesion 44 61?

Liver metastases 59 53

Extrahepatic metastases 11 42

Total 160 160CIM = conventional imaging modality; OctreoScan = indium-labelled octreotide scintigraphy; ? = not clear from original studySource: Lebtahi et al 199754

The authors of this study reported that the patient classification changed in 24% of casesand that the surgical strategy changed in 25% of cases. This was primarily because a largeproportion of patients thought not to have hepatic or extrahepatic metastases by CIMdid have such lesions. It was impossible to extract from the data reported in the study thenumber of patients who would have been in each category if scintigraphy alone had beenperformed.

In another report of the same study, which emaphsised the cost effectiveness aspects ofsomatostatin receptor scintigraphy, Kwekkeboom et al also reported on sensitivity ofOctreoScan.48 In 30 carcinoid patients, scintigraphy was more sensitive than CT scan,ultrasound and radiography. The results are shown in Table 8.

Table 8 Lesions detected by applied imaging techniques for 30 carcinoid patients

Imaging technique

Region No of lesions CT (%)Ultrasound

(%)Radiography

(%)OctreoScan

(%)

Head/neck 2 100 – – 100

Supraclavicular 2 – – – 100

Chest 15 67 – 20 100

Upper abdomen 17 46 20 – 100

Liver 12 86 82 – 58

Lower abdomen 21 20 – – 100CT = computed tomography; OctreoScan = indium-labelled octreotide scintigraphyNote: Percentages reflect the numbers of patients studied.Source: Kwekkeboom et al 199648

Treatment with somatostatin analogues is a therapeutic option for patients withmetastatic disease. Several of the studies referred to the fact that OctreoScan may bepredictive of response to treatment with octreotide. One study appeared to support thishypothesis57. This study compared the uptake of OctreoScan by carcinoid tumour lesionswith response to octreotide therapy. Of the 30 patients, 12 patients were assessedretrospectively and 18 patients assessed prospectively. Of the 27 patients who had apositive scintigraphy scan, 22 responded to somatostatin analogue treatment. None ofthe three patients who had a negative scan responded to treatment.

None of the studies reported on the acceptability of the test to patients.


Discussion

From review of the literature, an unbiased estimate of the sensitivity and specificity ofthe test could not be determined.

The most sensitive method for localisation of GEP tumours appeared to beintraoperative ultrasound plus palpation. No studies were available which directlycompared OctreoScan with this method.

In the study on the value of OctreoScan on management of gastrinomas, the addition ofthe test resulted in a change in management in 57 of 122 patients (47%).51 In this study,there was a high proportion of patients presenting for reassessment after failure ofsurgical cure (50 patients compared with 17 for initial evaluation). It is difficult to assesshow typical this would be of patients presenting in other clinics. It was noted in thisstudy that OctreoScan was useful for differentiating between haemangiomas andmetastases in the liver. CIM frequently cannot distinguish between the two types oflesions. OctreoScan on the other hand is only positive for metastatic lesions and notbenign haemangiomas. Even though the authors concluded that the test should be theinitial imaging study of choice in patients with gastrinomas, they were aware that ‘it stillremains unclear whether the routine use of SRS will either increase cure rate or extendsurvival in patients with Zollinger–Ellison syndrome’.

Because the use of octreotide therapy requires binding of the somatostatin analogue toreceptors on the tumour, a logical hypothesis would be that the response to octreotidetherapy may be predicted by the density of receptors on the tumours as indicated byOctreoScan. A small study, which was conducted both retrospectively and prospectively,appeared to support this hypothesis.57 However, a prospective study on an adequatenumber of patients could not be found. Octreotide is currently subsidised under thePharmaceutical Benefits Scheme for the treatment of carcinoid syndrome andpreliminary scanning with OctreoScan is not a condition for benefit.

What are the economic considerations?

The main focus of this report has been a systematic review of the effectiveness ofOctreoScan as a diagnostic test. It was not possible within the scope of this review to doa full economic evaluation of the technology. However, some comments can be made onthe costs and consequences of the use of this technology.

Costs

The following costs have been supplied by the Australasian and New ZealandAssociation of Physicians in Nuclear Medicine (Inc) in their position statement onOctreoScan directed to the Health Insurance Commission on 30 July 1996:

Recommended descriptors

(A) neuroendocrine imaging with OctreoScan — including planar imaging onone or more occasions and SPECT.

(B) neuroendocrine imaging with OctreoScan — including planar imaging onone or more occasions.

Costing for (A) ie whole body and SPECT


OctreoScan — 6.6 mCi (244 MBq) $1850.00Delivery fee $17.00Whole body imaging $300.00SPECT $110.00TOTAL $2277.00

Costing for (B) ie whole body planar

OctreoScan — 3.3 mCi (122 MBq) $1500.00Delivery fee $ 17.00Whole body imaging $300.00Radiopharmaceutical discounta –$60.00TOTAL $1757.00

a This test will be done infrequently, but in a small percent of cases (5–10%) two planar studies could be done at the same timewith a single 6.6 mCi dose. Thus an equivalent discount has been applied.

OctreoScan is considerably more expensive than CIM for the investigation of GEPtumours. This additional expenditure may be considered ‘value for money’ if theinformation gained from the investigation is of greater value than the additional cost.

If the data were available, the costs and consequences of the following diagnosticstrategies should be compared:

• CIM only;

• OctreoScan only;

• CIM followed by OctreoScan if metastatic lesions not detected by CIM;

• OctreoScan followed by CIM if metastatic lesions not detected by scintigraphy;and

• CIM and OctreoScan.

Based on an estimated incidence of 11 to 17 cases of GEP tumour per millionpopulation per year, there will be approximately 200 to 500 new cases per year inAustralia. There is a high level of uncertainty regarding the potential financial impact ofintroducing OctreoScan onto the MBS. It is unknown what proportion of these caseswill receive a scan or a repeat scan and the proportion of patients who would be treatedin the private sector. In several of the studies included above, a high proportion of thepatients being scanned were receiving a second or further follow-up scan.

As an indication of the financial implications of providing testing on the MBS, if weassume 350 cases per year, that 30% are treated in the private sector that each patientreceives an average of one scan and that the scan costs $2277, the total cost would be$239,085. This is on the assumption that the test is only used in patients withbiochemically proven disease.

Two studies have examined the cost-effectiveness of OctreoScan. The first studyattempted the complex task of estimating the incremental cost-effectiveness ofOctreoScan versus CIM.48 This paper evaluated the effects of adding OctreoScan to adiagnostic workup for a number of neuroendocrine tumours, including carcinoid (n =20), gastrinomas (n = 12) and insulinomas (n = 24). The data are based on patients who


were included in the University Hospital Rotterdam (UHR) trials and all of the abovequalifications concerning the selection of patients and the methodology of the trials applyto the cost-effectiveness data just as they do to the studies of effectiveness.

This study found that the scan was able to detect lesions that could not be identified byother forms of imaging in 15% of carcinoid patients and there was a 100% increase inthe total number of lesions. This was achieved at a cost of approximately an additional$900 per patient (the cost data having been collected in 1993). For gastrinoma patients,the addition of OctreoScan resulted in a doubling of primary and total tumours detectedat an additional cost of approximately $1000 and for insulinoma there was an increase inthe detection of tumours of 15% at a cost of approximately $500 per patient. The paperdoes not attempt to quantify how many of these lesions were clinically significant and theeffect of scanning on improvements in treatment planning or patient outcomes. Becauseof the lack of clinically meaningful outcomes data, it is difficult to assess whether theadditional expenditure is of value or not.

The second paper, Woodward et al, attempted to model the impact of scintigraphy inpatients with carcinoid tumour who were patients judged eligible for resection on thebasis of CIM58. The model predicted a net saving per patient scanned but the estimatesare highly sensitive to the relative costs of surgery and imaging. Because medical costs areconsiderably less expensive in Australia than in the United States, it is difficult toextrapolate from this data whether there would be net savings or costs in the Australiancontext. The study also suggests an average increase of only 0.02 ‘health status adjustedlife years’ (equivalent to 7.3 additional days in perfect health) achievable through the useof OctreoScan.

The model used in this paper is based on highly uncertain data. For example, the modelused an estimate of sensitivity of 90% based on Krenning’s reports and then assumedspecificity to be equal to sensitivity. The values for adjusting quantity of life for healthstatus were based on the opinion of one treating physician.

In the real world of medicine, cost-effectiveness will also be affected by the care withwhich patients are selected for OctreoScan, whether it is used in cost-effectivesequencing of a diagnostic strategy, or simply as an add-on to existing protocols, the rateat which the technology replaces exploratory surgery, and the frequency of palliative or‘heroic’ surgery undertaken in the presence of disseminated disease.

Implications for current resources

The number of persons diagnosed with GEP tumours each year in Australia is quitesmall (probably between 200 and 500 per year). Even if there was a major change in themethod of testing for the disease, this is unlikely to have a major impact on the overallusage of medical imaging facilities in Australia.


Other considerations

Consequences of testing

The possible consequences of testing are the detection of primary and metastatic lesions.The localisation of primary tumours may assist in allowing surgical resection of thelesion. Identification of metastatic lesions may result in patients avoiding surgery wherethere is no chance of surgical cure.

Although the evidence for the effectiveness of OctreoScan is very limited, the patientswho are most likely to benefit from scanning are those with a suspected tumour whohave negative or equivocal results on the basis of conventional imaging modalities, andthose with an apparently solitary lesion as shown by CIM and where the tumour is beingconsidered for resection.

Another group of patients who may potentially benefit from OctreoScan are those inwhom octreotide therapy is being considered. It appears that clinical response is relatedto the density of somatostatin receptors in the tumour and scanning may help to predictthose patients who could benefit from such therapy. This information is only useful if achange in patient management may result in patients receiving octreotide therapy andreducing the cost of therapy and adverse effects.

Access to technology

The test can be performed at any nuclear medicine facility. There does not appear to beany difficulty in having access to the technology.

Further research and development

None of the studies that were identified allowed for an unbiased estimate of thesensitivity or specificity of OctreoScan. The impact of scintigraphy on the outcome ofdisease could also not be assessed. These areas and also studies on the cost effectivenessof OctreoScan require further research to enable an informed decision on the value ofOctreoScan to be made.


Conclusions

Safety

OctreoScan appears to be safe at the currently recommended dosages.

Effectiveness

OctreoScan appears to have some theoretical advantages over other forms of imaging(for example it is able to image the entire body). However, there is a lack of data ofsufficient methodological quality to assess the true sensitivity and specificity ofOctreoScan.

Compared with existing methods of imaging, the test appears more sensitive, but the testhas not been compared in a blinded fashion with an acceptable gold standard and thetypes of tests with which it has been compared has varied, even within the same study.Although the possibility of false positive results (and therefore a specificity of less than100%) has been discussed, none of the trials reported data that would allow us tocalculate an estimate of specificity.

The major advantages of the technique are its ability to detect primary pancreatictumours not in the pancreas and metastatic lesions outside of the abdomen and chest.Because OctreoScan images the whole body, it may also detect an unsuspected MEN-1tumour.

OctreoScan appears to be less sensitive in the detection of insulinomas, because of thelack of receptor sites on such tumours. Insulinomas also tend to be solitary tumours, notrequiring a whole body technique.

Because the imaging of a tumour may not result in a change in clinical management, atest of greater sensitivity and specificity may not result in better outcomes for patients.There is some evidence that OctreoScan results in a change in management in aproportion of patients. However, there is no evidence that this results in increased curerates or survival time.

Cost-effectiveness

It is not possible to accurately estimate the cost-effectiveness of OctreoScan, because ofthe lack of validated data on the accuracy of the test and its influence on clinicaloutcomes.

Other considerations

None of the studies identified allowed for an unbiased estimate of the sensitivity orspecificity of OctreoScan. The impact of scintigraphy on the outcome of disease couldalso not be assessed. These areas and also studies on the cost-effectiveness of


OctreoScan require further research to enable an informed decision on the value ofOctreoScan to be made.


Recommendations

MSAC recommended that on the strength of evidence relating to OctreoScan, publicfunding should be supported for this diagnostic test:

• where there is a suspected gastro-entero-pancreatic neuroendocrine tumour,based on biochemical evidence, with negative or equivocal structural imagingfrom conventional radiology (CT or MRI); or

• where surgically amenable disease has been identified, based on biochemicalevidence and conventional imaging, in order to rule out further metastaticdisease.

Since there is currently insufficient evidence pertaining to the use of OctreoScan for thepurposes of determining whether octreotide therapy is a viable therapeutic option, publicfunding should not supported at this time for this use.


Appendix A MSAC terms of reference andmembership

The terms of reference of MSAC are to advise the Commonwealth Minister for Healthand Aged Care on:

• the strength of evidence pertaining to new and emerging medical technologiesand procedures in relation to their safety, effectiveness and cost-effectiveness andunder what circumstances public funding should be supported;

• which new medical technologies and procedures should be funded on an interimbasis to allow data to be assembled to determine their safety, effectiveness andcost-effectiveness; and

• references related either to new and/or existing medical technologies andprocedures.

The membership of MSAC comprises a mix of clinical expertise covering pathology,nuclear medicine, surgery, specialist medicine and general practice, plus clinicalepidemiology and clinical trials, health economics, consumers, and health administrationand planning:

Member Expertise

Professor David Weedon (Chair) pathology

Ms Hilda Bastian consumer health issues

Dr Ross Blair vascular surgery (New Zealand)

Mr Stephen Blamey general surgery

Dr Paul Hemming general practice

Dr Terri Jackson health economics

Professor Brendon Kearney health administration and planning

Mr Alan Keith Assistant Secretary, Diagnostics and Technology Branch,Commonwealth Department of Health and Aged Care(from 3 May 1999)

Dr Richard King gastroenterology

Dr Michael Kitchener nuclear medicine

Professor Peter Phelan paediatrics

Dr David Robinson plastic surgery

Ms Penny Rogers Assistant Secretary, Diagnostics and Technology Branch,Commonwealth Department of Health and Aged Care(until 3 May 1999)

Associate Professor John Simes clinical epidemiology and clinical trials

Dr Bryant Stokes neurological surgery, representing the Australian HealthMinisters’ Advisory Council (from 1 January 1999)

Dr Doris Zonta population health, representing the Australian HealthMinisters’ Advisory Council (until 31 December 1998)


Appendix B Supporting committee

Supporting committee for MSAC application 1003OctreoScan® scintigraphy for gastro-entero-pancreatic endocrine tumours

Dr Richard King (Chair)MBBS, FRACPDirector, General Medical and EmergencyMedicine, Southern Health Care Network,Victoria

member of MSAC

Dr Terri JacksonMA, PhDSenior Research Fellow,Health Economics Unit, Monash Universityand Manager of the Hospital ServicesResearch Group (HSRG).

member of MSAC

Dr Michael KitchenerMBBS, FRACPSenior Visiting Medical Specialist,Queen Elizabeth Hospital, Adelaide;Director, Nuclear Medicine,Dr Jones and Partners,St Andrews Hospital, Adelaide

member of MSAC

Dr Rodney HicksMBBS, FRACPDirector of Diagnostic Imaging, andDirector of Nuclear Medicine and PositronEmission Tomography,Peter MacCallum Cancer Institute, Melbourne

co-opted member


Appendix C Studies included in the review

Study Location/date Population QS

Age(years)/gender(M/F)

Study focus ProtocolReferencetest

Krenninget al 199633†

EuropeanMulticentreTrial (EMT) in15 institutes

August 1991 toMay 1993;follow-upupdated April1994

350 patients:67 ZES24 Insulinoma184 Carcinoid5 Glucagonoma8 VIPoma2 Somato-statinoma60 NFICT

1: U2: A3: U

Varied Localisationof tumourand detectionofmetastases

Varied CT, MRI,ultrasound,angiography,biopsy

Pauwelset al 199440

EMT (LouvainBelgium)

study date notreported

30 patients:7 Gastrinoma2 Insulinoma14 Carcinoid4 non-functioningpancreatic tumor2 MEN-11 motilinsecreting tumor

1:U2:A3:U

Notreported

Localisationof tumourand detectionofmetastases

198 (161–235) MBqoctreotidePlanar at 4 and24 hSPECT at 24 h

CT, MRI,abdominalultrasound,endoscopicultrasound,angiography

Kwekkeboomet al 1993,199646,47,48

UHR(Rotterdam,Netherlands)

June 1988 –September1990

30 patients withgut carcinoidtumors

1: U2: A3: U

Mean age61 (16–81)17 M;3 F

Localisationof tumouranddetection ofmetastasesDetection ofrecurrence

248 to 360 MBqoctreotidePlanar at 24 and48 h after injectionSPECT? notreported

CT, ultraso-nography,chest X-ray,bone scan

Termaniniet al 199749

NationalInstitutes ofHealth (NIH)(Bethesda,USA)June 94 toApril 96

122 patients withZES (includes 80patients also inGibril 199630)

1:A2:A3:A

Mean age53 (17–78)69 M;53 F

To assessthe effect ofSRS use inclinicalmanagement

222 MBq octreotideSPECT 35 min at 4and 24 hPlanar: 30 minwhole body scan at4 h; 10 min spotviews as needed

CT, MRI,ultrasound,angiography,bone scan

Lebtahiet al 199754

Paris, France

November1992 toSeptember1995

160 adults:38 Carcinoid44 other GEP

1: A2: A3: A

Mean age52 (49–55)88 M;72 F

Localisationof tumourand detectionofmetastasesDetection ofrecurrence

135 MBq octreotideSPECT abdominalin 64 patients(timing notreported)Planar at 4 h:anterior andposteriorabdominal images;24 h: anterior,posterior, lateraland oblique viewsof abdomen;anterior andposterior head,chest, pelvis

CT,abdominalultrasound,endoscopicultrasound,MRI, chestX-ray,abdominalangiography

† Overview summary of EMT study

QS — quality score viz:1 = consecutive studies of patients or random sample; 2 = all patients had both tests ; 3 = OctreoScan results and reference test results each interpretedblind to each otherA = adequate; I = inadequate; U = unclear


Abbreviations

CIM conventional imaging modalities

CT computed tomography

EMT European Multicentre Trial

GEP gastro-entero-pancreatic

OctreoScan OctreoScan scintigraphy

MBq megabequerel

MBS Medicare Benefits Schedule

MEN-1 multiple endocrine neoplasia type 1

MRI magnetic resonance imaging

MSAC Medicare Services Advisory Committee

NHMRC National Health and Medical Research Council

NIH National Institutes of Health (United States)

PET pancreatic endocrine tumour

SPECT single photon emission computerised tomography

TGA Therapeutic Goods Administration

UHR University Hospital, Rotterdam

ZES Zollinger–Ellison syndrome


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octreoscan® scintigraphy for gastro- entero-pancreatic ... · it is a nuclear medicine scan that...

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